The induction of mucosal immunity is very important in conferring protection against pathogens that typically invade via mucosal surfaces. Delivery of a vaccine to a mucosal surface optimizes the induction of mucosal immunity. The apparent linked nature of the mucosal immune system allows delivery to any mucosal surface to potentially induce immunity at others HOLMGREM, J, et al. Mucosal immunity and vaccines. Nat. Med. 2005, vol. 4, p. S45-53. Oral administration is a very straightforward and inexpensive approach to deliver a vaccine to the mucosal lining of the gut. However, vaccines administered by this route are subject to proteolysis in the gastrointestinal tract. Thus, dose levels for protein subunit vaccines are likely to be very high and the antigen may need to be protected from proteolysis for oral delivery to be efficacious STREATFIELD, S. J., et al. Mucosal immunization using recombinant plant-based oral vaccines. Methods. 2006, vol. 38, no. 2, p. 150-157.
As a consequence, orally delivered bacterin or subunit vaccines have not been proven to be efficacious since the antigens are generally modified by the stomach prior to presentation to the immune-responsive cells of the gut mucosa. A number of approaches have been tested to provide an oral delivery vehicle that would transit the stomach but most have been unsuccessful at the commercial scale.
Polymeric nanoparticles/microparticles have been proposed as a solution for the mucosal administration of conventional drugs. However they have not yet been developed commercially for vaccine delivery, although several polymeric delivery systems for mucosal vaccine delivery are currently being evaluated. The polymer-based approaches are designed to protect the antigen in the gut, to target the antigen to the gut-associated lymphoid tissue or to increase the residence time of the antigen in the gut through bioadhesion VYAS, S. P., et al. Implication of nanoparticles/microparticles in mucosal vaccine delivery. EXPERT REV. VACCINES. 2007, vol. 6, no. 3, p. 401-18. However, many hurdles must be overcome before these approaches become a practical reality. Among them, the use of organic solvents and materials for preparation of the particles can pose a threat to the vaccinated organism or the environment EP 2105129 A (HAREL)) In addition, preparation of the particles often increase the production cost to levels unaccepted for their use especially in the veterinary sector.
Since oral administration of protein subunit vaccines has to face proteolysis in the gastrointestinal tract, the dose levels for protein subunit vaccines are likely to be very high and the antigen may need to be protected from proteolysis for oral delivery to be efficacious. Obtaining a relatively high amount of antigen is both difficult and expensive if classical cell culture-based recombinant expression platforms are used. On the other hand, once an effective amount of unaltered antigen has reached the gut mucosa, the antigen must be targeted to the mucosal cells specialized in triggering the immune response JEPSON, M. A., et al. M cell targeting by lectins: a strategy for mucosal vaccination and drug delivery. Adv. Drug. Deliv. Rev. 2004, vol. 56, no. 4, p. 511-25.
The search for inexpensive production systems capable of producing large quantities of recombinant protein has resulted in the development of new technology platforms. The lepidopteran larvae-based baculovirus expression system is an inexpensive and high level expression system. An interesting aspect of this technology is sustained by different experiments showing that administration of either vaccines or biopharmaceuticals in crude purified extracts of lepidopteran larvae by the oral route to mice led to absorption by the mucosa at different levels, producing systemic activity of the active compound GONG, Z. Suppression of diabetes in non-obese diabetic (NOD) mice by oral administration of a cholera toxin B subunit-insulin B chain fusion protein vaccine produced in silkworm. vaccine. 2007, vol. 25, no. 8, p. 1444-51. XIAO, H. L., et al. Oral administration activity determination of recombinant osteoprotegerin from silkworm larvae. Molecular Biotechnology. 2007, vol. 35, no. 8, p. 179-84.
The baculovirus expression technology is widely used for production of recombinant vaccines based on virus-like particles (VLPs) or glycosylated viral antigens, both for human and veterinary use. Some of these products are on the market. Examples are the human papillomavirus vaccine Cervarix® commercialized by GSK MONIE, A., et al. Cervarix: a vaccine for the prevention of HPV 16, 18-associated cervical cancer. Biologics. 2008, vol. 2, no. 1, p. 97-105. or the protective vaccines against Porcine Circovirus 2 marketed by Intervet (Merck Animal Health)—Circumvent PCV® and Porcilis PCV® GRAU-ROMA, L., et al. Recent advances in the epidemiology, diagnosis and control of diseases caused by porcine circovirus type 2. Vet. J. 2011, vol. 187, no. 1, p. 23-32.
Different authors have shown that VLPs produced by the baculovirus expression technology are highly efficient vehicles for delivering heterologous cytotoxic T lymphocytes epitopes to the MHC-I pathway because they can induce potent immune responses in the absence of exogenous adjuvants. Although these immunostimulatory properties were first completely attributed to the particulate structure of the VLPs, it has been shown that the adjuvant effect of these particles is dependent on the presence of active BVs HERVAS-STUBBS, S., et al. Insect baculoviruses strongly potentiate adaptive immune responses by inducing type I IFN. J. Immunol. 2007, vol. 178, no. 4, p. 2361-69. which are concomitant to the production process, making antigens expressed by baculovirus unique vaccine candidate products.
The present invention relates to solve technological, environmental, and economical problems that currently hamper development and marketing of vaccines or biopharmaceuticals.